OPTN M98K - GET-Evidence



(OPTN Met98Lys)

Short summary

This variant was initially reported to be a risk factor for glaucoma, but subsequent reports have failed to find a statistically significant association. It may have a modifier effect, with carriers of the variant having lower intraocular pressure on average — pressures that might be considered normal in other individuals would be abnormally high for carriers of this variant.

Variant evidence

Other variants in this gene are associated with the disease, but Polyphen 2 predicts benign effect.

Functional -

contradictory reports for association with primary open-angle glaucoma, pooled data has no statistically significant association

See Rezaie T et al. 2002 (11834836), Melki R et al. 2003 (14627677), Jia LY et al. 2009 (19145250).

Familial -
Clinical importance
Severity 3

Late onset, progressive vision loss

Treatability 3

Glaucoma has an established treatment which involves reducing intraocular eye pressure. However Rezaie et al observe that carriers of this variant had normal intraocular pressure, so it may not respond to standard treatment.

See Rezaie T et al. 2002 (11834836).

Penetrance 3

See Rezaie T et al. 2002 (11834836).



Moderate clinical importance, Uncertain pathogenic

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Melki et al. and Jia et al. findings (no association with primary open-angle glaucoma) contradict the high significance association with primary open-angle glaucoma reported by Rezaie et al.

Simple pooling of their findings and applying a two-tailed Fisher’s Exact test finds a p-value of 0.53, which seems to indicate no causal association of this variant with glaucoma.

Total cases/controls case+ case– control+ control– p-value odds ratio
Primary Open Angle Glaucoma (Adult Onset)
76 562 64 537 0.5299 1.135


Allele frequency

  • A @ chr10:13152400: 6.1% (660/10758) in EVS
  • A @ chr10:13192405: 5.5% (7/128) in GET-Evidence
  • Frequency shown in summary reports: 6.1% (660/10758)


Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Héon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PubMed PMID: 11834836.

This study looked at adult-onset primary open-angle glaucoma and variants in OPTN. This variant was seen in 8 of 45 familial cases and in 15 of 124 sporadic cases.

Within this group of 169 subjects, M98K was observed in 8 of 45 (17.8%) familial and 15 of 124 (12.1%) sporadic individuals with glaucoma. It was seen in 9 of 442 Caucasian control chromosomes. Assuming the controls are 9 heterozygotes, comparing case vs. controls under a dominant hypothesis, we have: case+: 23, case-: 146, control+: 9, control-: 212. This is a p-value of 0.0012.

These case/control numbers indicate a ~3x risk for glaucoma compared to non-carriers. Assuming an average lifetime risk of 2.5%, we estimate carriers have an increased attributable risk of 5.4% (total of ~8%).

Cases/controls case+ case– control+ control– p-value odds ratio
Primary Open Angle Glaucoma (Adult Onset)
23 146 9 212 0.0012 3.711


Melki R, Belmouden A, Akhayat O, Brézin A, Garchon HJ. The M98K variant of the OPTINEURIN (OPTN) gene modifies initial intraocular pressure in patients with primary open angle glaucoma. J Med Genet. 2003 Nov;40(11):842-4. PubMed PMID: 14627677; PubMed Central PMCID: PMC1735315.

These authors conclude that M98K has a modifier effect and is not a risk factor for primary open-angle glaucoma (POAG) by itself.

French POAG cases, case+: 11, case-: 226. French controls, cont+: 5, cont-: 105. Moroccan POAG cases, case+: 6, case-: 50, Moroccan controls: cont+: 5, cont-: 55. These numbers indicate no increased incidence of this variant in POAG cases for either French, Moroccan, or combined groups.

They observe lower intraocular pressure in M98K carriers and hypothesize that M98K could be a modifier of the intraocular pressure — not necessarily increasing the risk of disease, but what might be considered normal intraocular pressure in noncarriers could be unusually high & pathogenic for an M98K carrier.

Cases/controls case+ case– control+ control– p-value odds ratio
Primary Open Angle Glaucoma (Adult Onset)
17 276 10 170 1.0000 1.047


Jia LY, Tam PO, Chiang SW, Ding N, Chen LJ, Yam GH, Pang CP, Wang NL. Multiple gene polymorphisms analysis revealed a different profile of genetic polymorphisms of primary open-angle glaucoma in northern Chinese. Mol Vis. 2009;15:89-98. Epub 2009 Jan 16. PubMed PMID: 19145250; PubMed Central PMCID: PMC2622715.

These authors looked at variants in MYOC, OPTN, WDR36, and APOE in Chinese patients with primary open-angle glaucoma (POAG). While they report a six-variant model with statistically significant association to POAG including this variant, their data for this variant alone has no statistically significant association.

Cases: Hom M98K: 3, Het: 33, Hom wildtype: 140. Controls: Hom M98K: 3, Het: 42, Hm wildtype: 155. Case/control numbers for Fisher’s Exact combine these under a dominant hypothesis.

Cases/controls case+ case– control+ control– p-value odds ratio
Primary Open Angle Glaucoma (Adult Onset)
36 140 45 155 0.7064 0.886



hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het A @ chr10:13152400


hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr10:13152400


hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr10:13152400


hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het A @ chr10:13152400


hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
het A @ chr10:13152400


huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr10:13152400


GS18501 - var-GS18501-1100-36-ASM
het A @ chr10:13192406


GS19025 - var-GS19025-1100-36-ASM
het A @ chr10:13192406


GS19649 - var-GS19649-1100-36-ASM
het A @ chr10:13192406


GS19669 - var-GS19669-1100-36-ASM
het A @ chr10:13192406


GS19703 - var-GS19703-1100-36-ASM
het A @ chr10:13192406


Other external references

  • rs11258194
  • Score: 0.031 (benign)

Other in silico analyses

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 3

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Gene search

"GENE" or "GENE A123C":

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